Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; S. Emily Bachert, MD, associate pathologist, Brigham and Women’s Hospital, Boston; Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Divya Sharma, MD, associate professor, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center; and Paula Toro, MD, pathology resident, Cleveland Clinic.
Comprehensive analysis of SWI/SNF complex-deficient undifferentiated carcinoma of the pancreas
November 2024—Inactivating alterations in switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex subunits have been described in multiple tumor types. Recent studies focused on SMARC subunits of this complex to explain their relationship with tumor characteristics and therapeutic opportunities. Pancreatic cancer with these alterations has not been well studied, although isolated cases of undifferentiated carcinomas have been reported. The authors conducted a study in which they screened 59 pancreatic undifferentiated carcinomas for alterations in SWI/SNF complex-related proteins or genes, or both (SMARCB1 [BAF47/INI1], SMARCA4 [BRG1], and SMARCA2 [BRM]) using IHC or next-generation sequencing. Cases with alterations in SWI/SNF complex-related proteins or genes were compared with cases without alterations, as well as with 96 conventional pancreatic ductal adenocarcinomas (PDAC). Mismatch repair and PD-L1 protein expression were also evaluated in all tumor groups. Thirty of 59 (51 percent) undifferentiated carcinomas had a loss of SWI/SNF complex-related protein expression or gene alteration. Twenty-seven of 30 (90 percent) SWI-/SNF-deficient undifferentiated carcinomas had rhabdoid morphology versus nine of 29 (31 percent) SWI-/SNF-retained undifferentiated carcinomas (P<.001). All of the former expressed cytokeratin, at least focally. Immunohistochemically, SMARCB1 protein expression was absent in 16 of 30 (53 percent) cases, SMARCA2 in four of 30 (13 percent), and SMARCA4 in four of 30 (13 percent). SMARCB1 and SMARCA2 protein expression were absent in one of 30 (three percent). Five of eight (62.5 percent) SWI-/SNF-deficient undifferentiated carcinomas that displayed loss of SMARCB1 protein expression by IHC were found to have corresponding SMARCB1 deletions by next-generation sequencing. Analysis of canonical driver mutations for PDAC in these cases showed KRAS (two of five) and TP53 (two of five) abnormalities. The median combined positive score for PD-L1 (E1L3N) was significantly higher in the undifferentiated carcinomas with or without SWI/SNF deficiency than in the conventional PDACs (P<.001). SWI-/SNF-deficient undifferentiated carcinomas were larger (P<.001) and occurred in younger patients (P<.001). Patients with SWI-/SNF-deficient undifferentiated carcinoma had worse overall survival compared with patients with SWI-/SNF-retained undifferentiated carcinoma (P=.004) and PDAC (P<.001). The findings from this study demonstrate that SWI-/SNF-deficient pancreatic undifferentiated carcinomas are frequently characterized by rhabdoid morphology and exhibit highly aggressive behavior, and they have a negative prognostic impact. Those with SMARCB1 deletions frequently appear to be KRAS wild type. Innovative developmental therapeutic strategies targeting this genomic basis of the SWI/SNF complex and the therapeutic implications of EZH2 inhibition (NCT03213665), SMARCA2 degrader (NCT05639751), and immunotherapy are being investigated.
Yavas A, Ozcan K, Adsay NV. SWI/SNF complex-deficient undifferentiated carcinoma of the pancreas: Clinicopathologic and genomic analysis. Mod Pathol. 2024;37(11). doi.org/10.1016/j.modpat.2024.100585
Correspondence: Dr. Olca Basturk at [email protected]
Utility of whole slide imaging for intraoperative consultation
Review of digital whole slide images using specific systems is approved for primary diagnosis in the United States but has not been implemented for intraoperative consultation. The authors conducted a study to evaluate the safety of whole slide imaging and to compare the efficiency of whole slide images (WSIs) and glass slides for intraoperative consultation. For the study, 91 cases previously submitted for frozen section evaluation were randomly selected from eight anatomic pathology subspecialties. Glass slides from these cases were scanned on a Leica Aperio AT2 scanner at 20 times magnification (0.25 μm/pixel). The slides were deidentified, and a short relevant clinical history was provided for each. Nine board-certified general pathologists who do not routinely establish primary diagnoses using WSIs reviewed the images using Leica Aperio ImageScope viewing software. After a washout period of two to three weeks, the pathologists reviewed the corresponding glass slides using the Olympus BX43 light microscope. They recorded the diagnosis and time to diagnosis. For both the WSIs and glass slides, the authors evaluated intraobserver concordance, time to diagnosis, and specificity and sensitivity compared to the original diagnosis. The authors found that the rate of intraobserver concordance between glass slide and WSI results was 93.7 percent. The mean time to diagnosis was 1.25 minutes for glass slides and 1.76 minutes for WSIs (P<.001). The specificity was 91 percent for glass slides and 90 percent for WSIs, and the sensitivity was 92 percent for glass slides and 92 percent for WSIs. Time to diagnosis was longer with WSIs than with glass slides, as scanning glass slides and uploading the data to whole slide imaging systems takes time. The authors concluded that reviewing WSIs appears to be a safe alternative to reviewing glass slides. Furthermore, whole slide imaging can be used to maintain pathology operations remotely during a public health emergency and facilitate subspecialty histopathology services in locations that are difficult to reach.
Shehabeldin A, Rohra P, Sellen LD, et al. Utility of whole slide imaging for intraoperative consultation: Experience of a large academic center. Arch Pathol Lab Med. 2024;148(6):715–721.
Correspondence: Dr. Phyu P. Aung at [email protected]
Histopathologic and clinical characterization of brentuximab vedotin-associated rash
Rash is one of the commonly observed adverse events with use of brentuximab vedotin, a CD30-targeted antibody-drug conjugate used to treat cutaneous T-cell lymphoma. However, clinical and histopathologic characterization of brentuximab vedotin-associated rash (BVAR) is limited. Distinguishing BVAR from a patient’s underlying cutaneous T-cell lymphoma (CTCL) can be challenging and can lead to treatment interruptions and delays. The authors performed a clinical and histopathologic retrospective characterization of BVAR from a single institution. Using polymerase chain reaction (PCR) and T-cell receptor high-throughput sequencing (TCR-HTS), they isolated skin biopsy specimens from rash clinically suggestive of BVAR that also lacked a dominant TCR clone. A retrospective evaluation of 26 biopsy specimens from 14 patients was conducted. Clinical features of BVAR included predominantly morbilliform or maculopapular morphology, delayed onset, and a trend toward classification as moderate to severe, often requiring oral steroids. Most histopathologic specimens (25 of 26) showed spongiotic dermatitis as the primary reaction pattern. Many cases showed subtle findings that supported a background interface or lichenoid eruption. Langerhans cell microabscesses were seen in 25 percent of specimens, and eosinophils were present in more than 50 percent. Focal features mimicking CTCL were present but not prominent. In 17 specimens with IHC, the CD4:CD8 ratio in intraepidermal lymphocytes was relatively normal (1–6:1) in 65 percent (11 of 17) and 1:1 in 35 percent (six of 17), demonstrating a trend toward increased CD8-positive cells compared with baseline CTCL. The authors identified features that can help distinguish BVAR from CTCL, which can, in turn, help guide clinical management.
Narala S, Saleem A, Brown RA, et al. Histopathologic and clinical characterization of brentuximab vedotin-associated rash. Am J Surg Pathol. 2024;48(9):1131–1137.
Correspondence: Dr. Saisindhu Narala at [email protected]
Clinical behavior of papillary thyroid carcinoma tall cell subtype and high-grade differentiated thyroid carcinoma tall cell phenotype
Papillary thyroid carcinoma tall cell subtype is a potentially aggressive histotype. The latest World Health Organization classification introduced a novel class of tumors—namely, high-grade differentiated thyroid carcinoma (HGDTC), which is characterized by an elevated mitotic count or necrosis, or both, and can exhibit a tall cell phenotype (HGDTC-TC). The authors conducted a study in which they analyzed clinical outcomes in a large retrospective cohort of 1,456 consecutive thyroid carcinomas with a tall cell phenotype, including papillary thyroid carcinoma tall cell subtype (PTC-TC) and HGDTC-TC. They found that HGDTC-TC is uncommon, accounting for 5.3 percent (77 of 1,379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumor size, angioinvasion, gross extrathyroidal extension, higher American Joint Committee on Cancer (AJCC) pT stage, positive resection margin, and nodal metastasis (P < .05). Compared with PTC-TC, HGDTC was associated with significantly decreased disease-specific survival, locoregional disease-free survival, and distant metastasis-free survival (P<.001). The 10-year disease-specific survival was 72 and 99 percent, 10-year locoregional disease-free survival was 61 and 92 percent, and 10-year distant metastasis-free survival was 53 and 97 percent, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification of HGDTC-TC versus PTC-TC was an independent adverse prognostic factor for disease-specific survival, locoregional disease-free survival, and distant metastasis-free survival when adjusted for sex, age, angioinvasion, margin status, and AJCC pT and pN stage. Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features and a higher frequency of TERT promoter mutations (59 percent in HGDTC-TC versus 34 percent in PTC-TC), and it has a significantly worse prognosis. The authors concluded that HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumor necrosis and high mitotic count in the diagnosis and prognosis of differentiated thyroid carcinomas.
Ghossein R, Katabi N, Dogan S, et al. Papillary thyroid carcinoma tall cell subtype (PTC-TC) and high-grade differentiated thyroid carcinoma tall cell phenotype (HGDTC-TC) have different clinical behaviour: a retrospective study of 1456 patients. Histopathology. 2024;84(7):1130–1138.
Correspondence: Dr. Bin Xu at [email protected]
Grading of cytologic epithelial atypia in pancreatic mucinous cysts
Cytologic examination of epithelial cells in cyst fluids from pancreatic mucinous cysts is the optimal method for identifying high-grade atypia, which may represent histologic high-grade dysplasia (HGD) or invasive carcinoma, and thereby classify the cysts as high risk and warranting surgical resection. The authors investigated the use and prognostic value of cytologic low-grade atypia and high-grade atypia for diagnosing pancreatic neoplastic mucinous cysts after implementing cytologic criteria for high-grade atypia at their institution. A total of 1,322 pancreatic cyst fluid specimens were identified in the institution’s pathology database from January 2014 to December 2021. All pathology reports and relevant clinical data were reviewed in detail. Two hundred and thirty unique cysts (217 patients) contained neoplastic mucinous epithelia, of which 178 had low-grade atypia and 52 had high-grade atypia. Ninety-seven cysts had histologic follow-up—77 (79 percent) resections and 20 (21 percent) diagnostic surgical biopsies only. Moreover, 92 (95 percent) were confirmed neoplastic mucinous cysts, three were adenocarcinomas, and two were benign entities. Among the histologically confirmed neoplastic mucinous cysts, 58 had low-grade dysplasia and 34 had high-grade dysplasia. Fourteen of the latter also had invasive carcinoma. Sixty-three percent of cysts with high-grade atypia demonstrated at least high-grade dysplasia on follow-up compared to those with low-grade atypia (26 percent, P<.001). The sensitivity and specificity of high-grade atypia for classifying a high-risk cyst was 54 percent and 81 percent, respectively. Of the 230 cysts, 146 (64 percent) had corresponding next-generation sequencing results. Thirty-one percent of the cysts with high-grade atypia harbored a high-risk mutation (TP53, CDKN2A, or SMAD4) versus seven percent of cysts with low-grade atypia (P< .001). Among cysts without histologic confirmation, 25 percent of cysts with high-grade atypia had a high-risk mutation versus seven percent of cysts with low-grade atypia. The grade of cytologic atypia was predictive of overall survival and recurrence-free survival (P<.001 and P=.020, respectively). Implementation of cytologic criteria for high-grade atypia in pancreatic mucinous cysts has relatively low sensitivity but modest specificity for classifying high-risk cysts. Although high-risk mutations were more commonly found in cysts with high-grade atypia, their frequency was low overall. Therefore, evaluating the degree of cytologic atypia, which is predictive of patient survival, provides significant value and informs patient outcomes.
Zhang ML, Kwan MC, Pitman MB. Grading cytologic epithelial atypia in pancreatic mucinous cysts predicts patient survival: Correlation with histologic, molecular, and clinical follow-up. Mod Pathol. 2024;37. doi:10.1016/j.modpat.2024.100510
Correspondence: Dr. M. Lisa Zhang at [email protected]